title: N6-isopentenyladenosine improves nuclear shape in fibroblasts from humans with progeroid syndromes by inhibiting the farnesylation of prelamin A.
abstract: Hutchinson-Gilford progeria syndrome is caused by mutations in the lamin A/C gene that lead to expression of a truncated, permanently farnesylated prelamin A variant called progerin. The accumulation of progerin at the nuclear envelope causes mis-shapen nuclei and results in progeroid syndromes. Previous studies in cells from individuals with Hutchinson-Gilford progeria syndrome have shown that blocking of farnesylation of prelamin A ameliorates the nuclear shape abnormalities. Here we observed that an inhibitor of farnesyl diphosphate synthase, N6-isopentenyladenosine, impeded the farnesylation of prelamin A, causing a decrease in the frequency of nuclear shape abnormalities and redistribution of prelamin A away from the inner nuclear envelope. A combination of lovastatin and N6-isopentenyladenosine significantly improved nuclear shape in fibroblast cell lines from atypical progeria patients. These findings establish a paradigm for ameliorating the most obvious cellular pathology in lamin-related progeroid syndromes, and suggest a potential strategy for treating children with Hutchinson-Gilford progeria syndrome.
authors.affiliation: Dipartimento di Medicina e Chirurgia, Università of Salerno Facoltà di Medicina, Baronissi, Italy; Dipartimento di Farmacia, Università di Salerno, Fisciano, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Bifulco
authors.forename: Alba
authors.initials: A
authors.lastname: D'Alessandro
authors.forename: Simona
authors.initials: S
authors.lastname: Paladino
authors.forename: Anna M
authors.initials: AM
authors.lastname: Malfitano
authors.forename: Maria
authors.initials: M
authors.lastname: Notarnicola
authors.forename: Maria G
authors.initials: MG
authors.lastname: Caruso
authors.forename: Chiara
authors.initials: C
authors.lastname: Laezza
mesh_terms: D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002648:Child; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051228:Geranyltranstransferase / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D007541:Isopentenyladenosine / Q000494:pharmacology*; D034904:Lamin Type A; D008297:Male; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010937:Plant Growth Regulators / Q000494:pharmacology*; D011371:Progeria / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011498:Protein Precursors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D034904:Lamin Type A; D009687:Nuclear Proteins; D010937:Plant Growth Regulators; D011498:Protein Precursors; D012333:RNA, Messenger; C090764:prelamin A; D007541:Isopentenyladenosine; D051228:Geranyltranstransferase
keywords: Hutchinson-Gilford progeria syndrome; N6-isopentenyladenosine; farnesyl diphosphate synthase; mevalonate pathway; prelamin A